Photochemistry Of Frusemide

There have been a number of studies of the photodegradation of frusemide with some apparent variation in the results reported.4"9 The differences in outcomes from the various studies are due to differences in irradiation conditions, such as the wavelength range, the concentration of frusemide and the solvent used, as well as the presence or absence of oxygen in the system. In our laboratory the approach has been to irradiate solutions which have an absorbance of about 1 at the Vm of the absorbing compound. Such a concentration usually permits direct spectrophotometric and chromatographic analysis of the irradiated solution. The presence of oxygen frequently leads to a more complex array of photoproducts due to the fact that oxygen is an efficient radical scavenger. Thus initial studies performed under a nitrogen atmosphere may provide a less complex product mixture which is easier to analyse.

The chlorine substituent is a major factor in the photochemistry of the diuretics, as dehalogenation occurs quite efficiently upon irradiation of the drugs in solution. The concomitant spectral changes are very slight and are not very useful for following the progress of the photoreaction, as shown for frusemide in Figure 2. The release of the chloride ion and the concomitant increase in acidity can be detected by potentiometric titration as

Figure 2 UV absorption spectra offrusemide solution in oxygen-free methanol after times of irradiation.

Figure 2 UV absorption spectra offrusemide solution in oxygen-free methanol after times of irradiation.

shown in Figure 3. The solvent clearly affects the nature of the reaction when aerated solutions are irradiated.5

Oxygen-free solutions of frusemide in methanol produced hydrogen and chloride ions with a quantum yield of 0.40 ± 0.08. In aqueous solution (containing 25% methanol because of the low solubility of frusemide in water) complete dechlorination was also observed with the same quantum yield. In oxygenated solutions, chloride production was inhibited more than H+ in methanol. Accompanying studies on oxidation photosensitized by frusemide show that it is an effective generator of singlet oxygen in methanol solutions but not in aqueous buffer at pH 7. Free radicals production is observed in deaerated solutions by the addition of a polymerizable monomer such as acrylamide, and is associated with the dechlorination process.

Figure 3 Yield of chloride and hydrogen ions in the photolysis of frusemide (5 x 10~4 M) in solution saturated with nitrogen (*) or oxygen ( •). Solvents: for (a) and (c) methanol; for (b) and (d) water-methanol 3:1.

Further investigation of the photosensitizing behaviour of frusemide in aqueous solution revealed that it is the neutral molecule which is effective in generating singlet oxygen and free radicals. With a pKa of 3.9 at 20°C, the drug is completely in the anionic form at pH 7.0 and both its photosensitizing ability and photodegradation are greatly diminished. The variation of photooxidation rate with pH followed a sigmoidal curve with an inflection corresponding to the apparent pKa of the photosensitizer in the system. This study was performed in surfactant solutions to overcome the poor solubility of frusemide, but it also demonstrated that the apparent pKa of the drug can be shifted according to the charge carried by the surfactant.

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